Electronic health record (EHR)-linked biobanks are uniquely positioned for genomic discovery and for implementing genomic medicine to improve patient care. In eMERGE I, we leveraged an EHR-linked biobank, high-density genotyping data, and electronic phenotyping algorithms to discover 29 genetic loci associated with cardiovascular traits. In eMERGE II we began implementing genomic medicine by conducting an EHR-based randomized clinical trial of disclosing genomic risk of coronary heart disease and incorporating pharmacogenomic information in the EHR with linkage to clinical decision support. In eMERGE III; we propose to build on our prior work to conduct a genomic medicine implementation project to establish mechanisms for return of actionable findings from targeted sequencing of 100 disease-relevant genes. Focusing on two common genetic disorders-familial hypercholesterolemia (FH) and familial colorectal cancer (CRC)-we will begin to translate genomic discovery and implementation efforts in eMERGE to impact public health. We will obtain informed consent from 3000 participants of Mayo Clinic biobanks in Rochester MN and Phoenix AZ who have moderate to severe hypercholesterolemia or colon polyps. DNA will be sent for CLIA-certified targeted sequencing of 100 disease genes. We will use state-of-the-art methods to classify variant pathogenicity, finalize actionable variants for return, examine near-term outcomes, economic implications and behavioral and psychosocial consequences of such return. We will also conduct genomic discovery leveraging a network-wide data set of ~25,000 individuals with sequence data and an existing network-wide data set of ~50,000 individuals with high-density genotype data linked to the EHR. We will exploit the unique potential of the EHR to assess pleiotropy using novel approaches. In partnership with Mountain Park Health Center, a primary care practice that serves a minority population of Mexican Americans in Phoenix AZ, we will contribute high-density genotyping and phenotype data on 1000 Hispanics for genomic discovery and pilot mechanisms for implementing genomic medicine at this site.